Nedaplatin-based chemotherapy or cisplatin-based chemotherapy combined with intensity-modulated radiotherapy achieve similar efficacy for stage II-IVa nasopharyngeal carcinoma patients

This retrospective study compared the efficacy and safety of nedaplatin-based chemoradiotherapy and cisplatin-based chemoradiotherapy in stage II-IVa nasopharyngeal carcinoma (NPC) patients. Patients treated with cisplatin-based or nedaplatin-based chemoradiotherapy between January 2012 and December 2015 were evaluated. Survival was estimated by the Kaplan‒Meier method and compared by the log-rank test. Multivariate analysis was performed using the Cox proportional hazards model. A cohort of 538 NPC patients was enrolled. There were no significant differences in the 5-year overall survival (OS), progression-free survival (PFS), locoregional relapse-free survival (LRRFS), or distant metastasis-free survival (DMFS) between the cisplatin and nedaplatin groups. During the whole treatment course, patients in the cisplatin group had higher incidences of grade 3‒4 vomiting and anorexia, while patients in the nedaplatin group had higher incidences of grade 3‒4 leucopenia and mucositis. In terms of late toxicities, patients in the cisplatin group had a higher incidence of xerostomia. In multivariate analysis, T stage, N stage, and clinical stage were prognostic factors for OS, PFS, and DMFS. In subgroup analyses, nedaplatin-based chemotherapy achieved comparable treatment outcomes in specific populations stratified by age, sex, ECOG PS score and clinical stage. Cisplatin and nedaplatin are effective choices for stage II-IVa NPC patients, with a different spectrum of side effects.


Materials and methods
Patient selection. We retrospectively analysed data from patients with newly diagnosed NPC between January 2012 and December 2015 at the Second Xiangya Hospital, Central South University. All data were extracted from the electronic medical history system of the hospital. The primary tumour site was evaluated by contrast-enhanced magnetic resonance imaging (MRI). Distant metastasis was evaluated by X-ray chest radiography, ultrasonography of the abdominal region and bone scintigraphy or contrast-enhanced computed tomography (CT) of the chest and abdominal region and bone scintigraphy. The inclusion criteria were as follows: (1) pathologically diagnosed nasopharyngeal squamous cell carcinoma; (2) stage II-IVa according to the 8 th edition of the Union for International Cancer Control/American Joint Committee on Cancer (AJCC) staging system; (3) use of induction chemotherapy + CCRT ± adjuvant chemotherapy for stage III-IVa patients and use of CCRT or radiotherapy ± adjuvant chemotherapy for stage II patients; (4) no previous treatment with radiotherapy, chemotherapy or anti-epidermal growth factor receptor targeted therapy after the diagnosis; and (5) Eastern Cooperative Oncology Group (ECOG) performance status score ≤ 1. The exclusion criteria were as follows: (1) use of different types of platinum drugs in the induction, concurrent, or adjuvant chemotherapy phases; and (2) loss to follow-up within 48 months after treatment started.
The study was approved by the ethics committee of the Second Xiangya Hospital, Central South University, and the requirement to obtain informed patient consent was waived due to the nature of the study. All methods were performed in accordance with the relevant guidelines and regulations.
Radiotherapy. All patients were treated with IMRT using 6 MV X-rays on Varian 23EX or Varian Trilogy linear accelerators. Each patient was immobilized with a low-temperature thermoplastic film, and simulated positioning was performed on simulated CT. The total dose was as follows: 70-74 Gy/30-33 F to the planning target volume (PTV) of the gross tumour volume (GTVnx) and involved cervical lymph nodes (GTVnd), 60 Gy/2.0 Gy/30 F to the PTV of the high-risk region (CTV1), including the GTVnx and GTVnd, with a margin of 5-10 mm. As previously reported 18 , the CTV1 region covers the entire nasopharynx, inferior two-thirds of the sphenoid sinus, the anterior third of the clivus, the pterygoid fossae, the posterior third of the nasal cavity and maxillary sinuses, the retropharyngeal nodes, the parapharyngeal space, and the drainage area of the upper neck, and 56 Gy/1.87 Gy/30F was administered to the PTV of the low-risk region (CTV2), including CTV1, plus a margin of 3-5 mm, the lower neck, and the supraclavicular lymphatic drainage region. All patients received one fraction daily for 5 fractions per week. Dose constraints to adjacent critical organs were applied according to the Radiation Therapy Oncology Group (RTOG) 0225 protocol 19 . Chemotherapy. In the cisplatin group, the patients received induction and/or adjuvant chemotherapy with the regimen of docetaxel plus cisplatin (DP; docetaxel 75 mg/m 2 on day 1 and cisplatin 75 mg/m 2 d1 or 25 mg/ m 2 on days 1-3). During radiotherapy, the patients received concurrent cisplatin 100 mg/m 2 3-weekly for up to 3 cycles. In the nedaplatin group, the patients received induction and/or adjuvant chemotherapy with the regimen of docetaxel plus nedaplatin (DN; docetaxel 75 mg/m 2 on day 1 and nedaplatin 75 mg/m 2 d1 or 25 mg/m 2 on days 1-3). During radiotherapy, this group of patients received concurrent nedaplatin 100 mg/m 2 3-weekly for up to 3 cycles. In both groups, adjuvant chemotherapy was given to patients who were staged T4 or N3 or those with an inadequate concurrent chemotherapy dose (< 200 mg/m 2 ).
Toxicity evaluation and follow-up. Acute toxicities of chemotherapy and radiotherapy were graded during the whole treatment course, including the induction, concomitant, and/or adjuvant phases, according to the National Cancer Institute Common Toxicity Criteria for Adverse Events (CTCAE 5.0) and the Acute and Late Radiation Morbidity Scoring Criteria of the RTOG (Version 3.0) 20  www.nature.com/scientificreports/ as acute inflammation that occurred in the radiation field. Acute haematological toxicities were graded according to routine blood tests during the whole treatment course. Acute non-haematological toxicities, including digestive, liver and renal toxicities, were graded according to the blood test and medical records. Late toxicity, which was defined as toxicity that presented at least 6 months after the end of treatment, was recorded according to the outpatient or telephone follow-up records. All patients were followed up after the completion of the treatment, once every 3 months in the first 2 years, once every 6 months from the 3rd to the 5th year, and once yearly thereafter. Follow-up visits included physical examination, blood biochemistry profile measurement, chest radiography, abdominal ultrasound, endoscopy, and MRI or CT of the head and neck and abdomen as necessary.
Patients who did not return for follow-up were contacted via telephone to ascertain their survival status and long-term toxic effects. The last follow-up date was February 1, 2021, and the median follow-up period was 66 months (range: 8-106 months). Endpoints included 5-year overall survival (OS), progression-free survival (PFS), locoregional relapse-free survival (LRRFS), and distant metastasis-free survival (DMFS). OS was defined as the interval between the date of treatment initiation and the date of death from any cause or the last follow-up. PFS was defined as the interval between the date of treatment initiation and the date of disease progression, death, or the last follow-up. LRRFS was defined as the interval between the date of treatment initiation and the date of local or regional relapse. DMFS was defined as the interval between the date of treatment initiation and the date of distant metastasis.
Statistical analysis. Statistical analyses were performed using SPSS V26.0 software (SPSS Inc., Chicago, IL, USA) and R version 3.6.3 (R Foundation for Statistical Computing, https:// www.r-proje ct. org/). The characteristics of the patients were compared via the chi-square test or Fisher's exact test. Survival outcomes, including OS, PFS, LRRFS, and DMFS, were estimated by the Kaplan-Meier method and compared by the log-rank test and obtained 95% CIs using the Greenwood formula. Multivariate analysis and subgroup analysis of potential prognostic factors was estimated using the Cox proportional hazards model, and an interaction term between treatment methods and the potential prognostic factors was then added into the model to test their interaction effect for survival. In our study, treatment methods and other potential prognostic factors (sex [male or female] and age [< 50 years or ≥ 50 years], ECOG [0 or 1], and cancer stage [II-III or IVA-B]) were entered into the multivariate Cox proportional hazards regression model to test for their main effects, and an interaction term between treatment methods and the potential prognostic factors was then added into the model to test their interaction effect for survival. Two-sided P values < 0.05 were statistically significant.

Results
Baseline characteristics. There were 724 patients who were treated in our centre between January 2012 and December 2015. Of these patients, 538 patients were enrolled in the present study (Fig. S1). Among all the patients meeting the inclusion criteria, 54 patients were excluded because of inadequate follow-up. The patient and disease characteristics are listed in Table 1. Among all the patients, 189 (35.1%) patients were older than 50 years, 377 (70.1%) were male, and 292 (54.3%) were smokers. A total of 489 (90.9%) patients had an ECOG PS score of 0. According to the AJCC 8th edition staging system, the patients enrolled in the present study were divided into stage II (12.8%), stage III (61.5%), and stage IVa (25.7%). There were no statistically significant differences in the proportional distributions of age, sex, T stage, N stage, or clinical stage between the two groups. Of the 69 stage II patients enrolled, 28 received CCRT. Therefore, 497 (92.4%) patients in the whole cohort received CCRT. Of these patients, 342 (63.6%) patients had a dose reduction during CCRT, which was defined as receiving a total dose of cisplatin or nedaplatin < 200 mg/m 2 . The proportion of patients with dose adjustment was higher in the cisplatin group than in the nedaplatin group (67.1% vs. 56.9%, P = 0.024). In the cisplatin group, the dose reduction was primarily due to severe mucositis and its induced malnutrition (115/235, 48.9%) and bone marrow suppression (102/235, 43.4%). In the nedaplatin group, the dose reduction was mostly due to bone marrow suppression (61/107, 57%), followed by mucositis and malnutrition (35/107, 32.7%). A total of 477 (88.7%) patients received induction chemotherapy, while 462 (85.9%) patients received at least one cycle of adjuvant chemotherapy.
Survival outcomes. The median follow-up period was 66 months (ranging from 8 to 106 months). As shown in Fig. 1 and Table 2 Subgroup analysis. We performed subgroup analyses for OS, PFS, DMFS, and LRRFS in patients stratified by the following variates: age (< 50 or ≥ 50), sex (male or female), ECOG PS score (0 or 1), and disease stage (II-III or IVa). No interactions between these variates and treatment outcome were observed (Fig. S2), suggesting that nedaplatin-based chemotherapy could achieve comparable treatment outcomes among specific populations.

Prognostic factors.
To determine the factors affecting patient survival, we performed univariate and multivariate analyses to identify the factors predicting OS, PFS, LRRFS, and DMFS. The putative prognostic factors included sex, age, ECOG PS, smoking history, T stage, N stage, clinical stage, and drug type ( www.nature.com/scientificreports/ ate analysis, we found that T stage, N stage, and clinical stage were prognostic factors for OS, PFS, and DMFS. T stage was also a prognostic factor for LRRFS. ECOG PS was a prognostic factor for DMFS. Further multivariate analyses showed that clinical stage and N stage were independent predictive factors of OS, PFS, and DMFS. T stage was an independent predictive factor of PFS and LRRFS. Moreover, ECOG PS was an independent predictor of DMFS (Table 3, Fig. 2).
Toxicity. The treatment-related acute and late toxicities are listed in Table 4. Generally, patients in the cisplatin group had a higher incidence of non-haematological toxicities, while patients in the nedaplatin group had a higher incidence of haematological toxicities. The proportions of patients with grade ≥ 3 leucopenia and grade ≥ 3 neutropenia in the nedaplatin group were significantly higher than those in the cisplatin group (P = 0.015 and P = 0.007, respectively). The proportions of patients with grade ≥ 1 nausea, grade ≥ 1 vomiting, grade ≥ 3 vomiting, and grade ≥ 1 and grade ≥ 3 anorexia in the cisplatin group were significantly greater than those in the www.nature.com/scientificreports/ nedaplatin group (P < 0.001, P < 0.001, P = 0.002, P = 0.007, and P < 0.001, respectively). Although patients in the cisplatin group had a higher incidence of constipation (P = 0.024), the incidence of severe constipation was not significantly different between the two groups. The proportion of patients with grade ≥ 3 mucositis was significantly higher in the nedaplatin group than in the cisplatin group (P = 0.018). However, the incidences of acute kidney injury and cardiotoxicity were similar between the two groups. In terms of late toxicities, the incidences of ototoxicity and dysphagia were not significantly different between the two groups. However, patients in the cisplatin group had a higher incidence of xerostomia (P = 0.036).

Discussion
In the present study, we retrospectively analysed the treatment of LA-NPC patients with cisplatin-or nedaplatinbased chemotherapy combined with IMRT. Patients in the cisplatin and nedaplatin groups had similar survival rates. The differences in the 5-year OS, PFS, LRRFS, and DMFS rates between the two groups were not statistically significant. In terms of acute toxicity, there were different spectra of acute toxicities between the two groups. The incidence of haematological toxicities was significantly higher in the nedaplatin group, while that of gastrointestinal tract toxicities was significantly higher in the cisplatin group. Moreover, the incidence of xerostomia was higher in the cisplatin group. In multivariate analysis, we found that T stage, N stage, clinical stage, and ECOG PS were major prognostic factors, which was in accordance with previous reports [21][22][23] .
Cisplatin-based chemotherapy is the regimen most widely used in the treatment of metastatic 24 and locoregional advanced 6 NPC. The 5-year OS rate of stage III-IV patients after IC + CCRT was approximately 80.8% 25 . Some trials have reported that CCRT brings survival benefits to stage II patients, with a 5-year OS rate of 94.5% 26 . www.nature.com/scientificreports/ Although cisplatin-based chemotherapy brought benefits to NPC patients, it also resulted in increased toxicities, which decreased its tolerability and the quality of life of the patients. Nedaplatin is a second-generation platinum derivative with lower rates of renal and gastrointestinal toxicities than cisplatin. Due to its lower renal toxicity, nedaplatin does not require hydration in clinical use. During the past decade, there has been increasing evidence showing that nedaplatin is as effective as cisplatin in the treatment of NPC. In a retrospective study, Liu et al. 27 reported that nedaplatin combined with fluorouracil,   28 . In our study, we found that the 5-year PFS rates in the nedaplatin and cisplatin groups were 79.2% and 75.9%, the 5-year OS rates were 81.5% and 80.6%, and the 5-year DMFS rates were 82% and 81.2%, respectively, which were lower than the data from clinical trials. However, the 5-year LRRFS was comparable to that in the clinical trial. This    29 . Moreover, there are about 10% of patients who were excluded due to inadequate follow-up. Considering that the risk of disease relapse is very low for those patients who had no disease relapse at 48 months after the treatment, this group of patients may cause underestimation the actual survival rate in the whole cohort. In terms of toxicities, it was reported that the overall percentage of grade ≥ 3 adverse events was 73%, and approximately two-thirds of the patients discontinued concurrent cisplatin treatment 8 . In a retrospective study, Liu et al. 27 reported that the nedaplatin group had higher incidences of grade 3-4 neutropenia and thrombocytopenia, while the cisplatin group had higher incidences of grade 3-4 nausea, vomiting, and weight loss. It was reported in a prospective study that the incidence of grade 3-4 nausea and vomiting was significantly higher in the cisplatin group, although the incidence of haematological events was similar between the two groups 18 . Later, they reported in the secondary analysis that patients in the cisplatin group had a higher incidence of grade 3 and 4 auditory toxic effects than those in the nedaplatin group 28 . In the present study, we found that the frequency of grade 3 or 4 leucopenia was 27.51% (148/538), while it was significantly higher in the nedaplatin group. Our results indicated that the surveillance of haematological toxicities should be more emphasized in patients treated with nedaplatin-based chemotherapy in the real world. The frequency of grade 3 or 4 vomiting in the cisplatin group was 6.9%, which was also lower than previously reported rates. This may be attributed to splitting of the cisplatin dose. However, the incidence of hypoalbuminemia induced by vomiting and mucositis between the two groups had no statistical significance. In the present study, the incidence of acute renal toxicity was higher in the cisplatin group, with borderline statistical significance, which may be due to splitting of the cisplatin dose and adequate hydration before treatment. Regarding late toxicities, we found that the incidence of xerostomia was significantly higher in the nedaplatin group, and the incidence of ototoxicity was similar between the two groups. However, due to the limitation of follow-up data, we could not grade the severity of the toxicities.

P value for events grade ≥ 3 Any Grade Grade 1-2(%) Grade 3-4(%) Any Grade Grade 1-2(%) Grade 3-4(%) Haematological
Certainly, there were a few limitations to the study. First, the retrospective nature and long time span of the study may have introduced bias to the results. Second, the proportion of patients who received a dose adjustment in the nedaplatin group was higher than that in the cisplatin group, which may be a confounding factor. Third, the incidence and severity of some long-term toxicities, such as neurotoxicity, were not reported in the present study. Fourth, there were some clinical characteristics that play an important role in prognosis and treatment optimization, such as Epstein-Barr virus DNA and lactate dehydrogenase levels 30 , that were not taken into consideration. Finally, the results should be interpreted with caution when applying them to patients from nonendemic regions, such as Europe and America.
In conclusion, our study demonstrated that cisplatin-based chemotherapy and nedaplatin-based chemotherapy achieved comparable survival, with different toxicity profiles, in patients with NPC. Nedaplatin may be an alternative choice for NPC patients, particularly for those who are at high risk of severe gastrointestinal toxicities or who cannot tolerate cisplatin due to kidney morbidity.

Data availability
The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. www.nature.com/scientificreports/ Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/.